tbuckley/cabot-search huggingface dataset:
Immunological profile could be responsible of the unusual long-lasting cutaneous-only breast cancer recurrence: An observational study.
Authors: Joseba Rebollo, Ramón González-Manzano, Manuel Sureda, Elena Ma Martínez, Elena Monedero, Pedro Bretcha, Antonio Brugarolas
Journal: Journal of Clinical Oncology (2022)

e13000 Background: A small number of breast cancer patients develops long-lasting loco-regional cutaneous recurrent disease with a delayed appearance of systemic disease. We recently have observed a favourable immunological signature in one patient and thereafter we looked back to the institutional series to formulate a possible hypothesis. Methods: Two datasets of resistant and metastatic solid tumors (362 Agilent microarrays and 169 RNA sequencing), have been studied. Three immunological signatures have been applied (T-cell inflamed, Cytolysis and TMM) and patients with at least one positive signature have been identified. Results: Preliminary evidence identified, from our genomic and transcriptomic advanced breast cancer database (73 patients and 80 procedures), three patients (4%) with loco-regional only cutaneous recurrent disease. Two patients (#1 and #2) were Hormone Receptor-negative, HER2 receptor-positive with a long-lasting breast cancer cutaneous recurrence (57 and 42 months, respectively) until bone (#1) or visceral (pleura and liver) (#2) progression. Patient #3 is a Hormone Receptor-positive, HER2-negative breast cancer that has recently developed an ipsilateral cutaneous (breast) recurrence so we do not have a follow up. Patient #1 had 4 transcriptomic tests, patient #2 had 2 tests and #3 one test. Biopsies were obtained from cutaneous lesions. According to our database, 25 out 80 procedures (31.25%) showed at least one favourable immunological signature (Table). In patients #1 and #2 with consecutive genomic testing, the immunological profile got worse with the resistance to therapies before systemic progression. Conclusions: According to our observation, a positive immunological signature was associated with a loco-regional cutaneous breast cancer recurrence and an unusually prolonged course of the disease. This observation should be confirmed in larger trials with more patients. Immunotherapy might play a role in the management of this clinical situation. None of these 3 patients had a triple negative phenotype for which immunotherapy has been found active. Ayers et al. J Clin Oncol 2017; 127 (8):2930-2940. Yang et al. Clin Cancer Res 2020; 26(8):3296-3306. Manzano et al. BMC Cancer 2021: 432.[Table: see text]
Evaluation of the interplay between NASH and HFpEF in varied murine age groups
Authors: D Kucsera, N V Sayour, M Ruppert, T Radovits, A Fabian, A Kovacs, P Ferdinandy, ZV Varga
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union's Horizon 2020 Research and Innovation Programme, grant agreement no. 739593 New National Excellence Program of the Ministry of Human Capacities (ÚNKP-21-3-II) Introduction Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, left ventricular hypertrophy, left atrial enlargement and increased serum levels of NT-pro-BNP. HFpEF accounts for 50% of heart failure cases, and typically develops in patients with metabolic comorbidities. Non-alcoholic fatty liver disease and subsequent steatohepatitis (NAFLD, NASH) is the most common chronic liver disease developing due to obesity. Although clinical/epidemiological data exists in humans showing that NASH may lead to cardiac dysfunction per se, experimental data in this regard is lacking. Purpose We aimed to evaluate whether NASH is an independent factor of cardiac dysfunction and to investigate the age-dependent effects of NASH on cardiac function. Methods Middle aged (10 months old) and aged (24 months old) C57Bl/6J mice were fed either control diet or Choline Deficient (CDAA) diet over a period of eight weeks. Young (2 months old) mice were used as a control. Before termination, echocardiography was performed. Upon termination, organs were isolated for further analysis. Results CDAA diet lead to the development of NASH in both age groups, without inducing weight gain, allowing us to investigate the direct effects of NASH on cardiac function. Left ventricular end-diastolic volume (EDV) was increased in aged animals, compared to young and middle aged animals, suggesting increased ventricular pressure. Aged animals were characterized by increased posterior wall thickness (PWT) during diastole and by increased LV mass, indicating left ventricular hypertrophy. Assessment of ejection fraction showed an age-dependent decline. Pulse wave and tissue Doppler measurements showed no difference in E/e’ ratio between the groups. However, strain analysis showed that diastolic dysfunction developed only in aged mice due to NASH. Conclusion We conclude that there were no observed changes in cardiac diastolic function due to NASH when using standard echocardiographic evaluation; however, the more sensitive method of strain analysis with 2D speckle tracking was able to show evidence of diastolic dysfunction due to NASH in aging animals.
Molecular features of undifferentiated sarcoma of soft tissue and carcinoma.
Authors: Yuan Liu, Yingyi Wang, Rongrong Chen
Journal: Journal of Clinical Oncology (2022)

e23519 Background: Both undifferentiated sarcoma of soft tissue and undifferentiated carcinomas can arise in multiple tissue and are with an aggressive clinical course. While undifferentiated sarcomas that remain a diagnosis of exclusion and show extreme genomic complexity, less is known about undifferentiated carcinoma. Methods: Sixty-two patients diagnosed as undifferentiated sarcoma (n = 36, 10 bone/limbs, 9 abdomen, 9 pelvis, and 8 chest/intrathoracic) or carcinoma (n = 26, excluding undifferentiated carcinoma of nasopharynx and thyroid, 15 chest/intrathoracic, 8 abdomen, and 3 pelvis) were recruited in the study. Mutational analysis was performed by next-generation sequencing of 1021 tumor related genes, which enabled analysis of TMB and MSI as well. PD-L1 expression data was available in 24 patients. Results: Fifty-eight patients (93.5%, 58/62) had at least 1 mutation identified and 542 SNV, 115 CNV and 5 fusions were identified in total in the 62 patients. The top 5 mutant genes were TP53 (56.5%, 35/62), TERT (11.3 %, 7/62), SMARCA4 (9.7%, 6/62), LRP1B (9.7%, 6/62), and MLL2 (9.7%, 6/62). Interestingly, mutation in TP53 was more common in undifferentiated carcinoma (73.08%, 19/26) than sarcoma (44.44%, 16/36, p = 0.0377). Two ERBB2 CNV and 1 KIF5B-RET fusion were identified in 2 gastric carcinoma and 1 lung large cell carcinoma. However, no carcinoma but 2 sarcoma (1 polymorphic undifferentiated sarcoma in the limb and 1 undifferentiated small round cell sarcoma in the lung) showed MSI-H, with TMB as high as 22.08 and 65.28 respectively, while the median TMB was 3.84 mutations/Mb. Among the 24 patients with PD-L1 data, 16 were &gt; 1%, and 5 were &gt; 50%, with no significant difference between undifferentiated carcinoma and sarcoma. Conclusions: In spite of the genome complexity in undifferentiated sarcoma of soft tissue and carcinoma, there was limited actionable mutations in these two aggressive tumors. However, immunotherapy should be considered since over half of these patients were PD-L1 positive and nearly a quarter of them had high PD-L1 expression.
BRCA1/2 genes mutations frequency in patients with various histological types of ovarian cancer (data for South of Russia).
Authors: Natalya N. Timoshkina, Natalia A. Petrusenko, Dmitry Yu. Gvaldin, Madina A. Gappoeva, Sergey E. Kavitskiy, Maria A. Cherkes, Ekaterina V. Verenikina, Denis S. Kutilin
Journal: Journal of Clinical Oncology (2022)

e17548 Background: About 10-15% of malignant ovarian tumors (OC) are associated with hereditary diseases, and about 65-85% of hereditary OC have a mutation in BRCA1/2 genes. The aim of the study was to analyze BRCA1/2 genes hereditary mutation spectrum in patients in the South of Russia diagnosed with OC. Methods: We used EDTA venous blood and FFPE-blocks of 324 patients with histologically verified epithelial OC (T1-3cNx-1Mx-1, stage I-IV). BRCA1 gene mutations (185delAG, 300T &gt; C, 2080delA, 4153delA, 5382insC, 3819delGTAAA, 3875delGTCT) and BRCA2 gene mutations (6174delT) were determined by real-time PCR. Results: The most common types of OC were poorly differentiated serous carcinoma (high degree of malignancy) - 75.6%, well-differentiated serous carcinoma (low degree of malignancy) - 13%, mucinous tumors - 2.8%, endometrioid tumors - 4.3%, clear cell adenocarcinomas - 4.3%. BRCA1/2 genes mutations were found in 52 (16%) patients with OC. The frequency of detected BRCA1/2 genes mutations was: 5382insC - 53.8%, 4153 delA - 9.6%, 300T &gt; G - 21.2%, 2080delA - 7.7%, 185delAG - 3.8%, 6174delT - 3.8%. 3819delGTAAA and 3875delGTCT mutations were not found in the BRCA1 gene. All carriers were confirmed to have the same mutations in the tumor. There were no cases of sporadic changes in BRCA1/2. BRCA1 mutation carriers prevailed in the group of high-grade serous carcinoma patients (11.1%), where all cases of BRCA2 gene mutations were identified. In the group of low-grade serous carcinoma patients, the mutation rate was 1.5%, in the endometrioid adenocarcinomas group - 0.6%, in the mixed epithelial tumors group - 2.8%. In the group of patients with mucinous tumors, mutations were not detected. Conclusions: Thus, frequency of BRCA1/2 gene mutations in OC patients living in the South of Russia was 16.0%. Distribution of mutation types in the BRCA1 gene, with a predominance of 5382insC (53.8%) and 300T &gt; G (21.2%), corresponded to their occurrence ratio in the European populations. BRCA1/2 gene mutations were registered more often in the group of high-grade serous carcinoma patients.
Mapping EAU guideline practice variations across Europe: An audit of ADT before surgery in locally advanced and high-risk prostate cancer in 6315 cases across 31 European countries
Authors: S. MacLennan, N. Azevedo, A. Briganti, E. Duncan, J. Dunsmore, L. Fullwood, N. Lumen, K. Plass, M.J. Ribal, M.J. Roobol, N. Schouten, E.J. Smith, T.A. Skolarus, J.M.O. N'Dow
Journal: European Urology (2022)
ETMR-12. Novel cell models of CNS tumors with BCOR fusion or internal tandem duplication suggest FGFR and PDGFR as promising therapy targets
Authors: Dominik Kirchhofer, Daniela Lötsch-Gojo, Lisa Gabler, Carola N Jaunecker, Martin Piontek, Lisa Mayr, Bernhard Englinger, Christine Pirker, Thomas Mohr, Anna Lämmerer, Felix Schmitt-Hoffner, Bernd Boidol, Stefan Kubiceck, Andreas Peyrl, Amadeo A Azizi, Christian Dorfer, Christine Haberler, Marcel Kool, Walter Berger, Johannes Gojo
Journal: Neuro-Oncology (2022)

Abstract Central nervous system (CNS) tumors with BCOR internal tandem duplications (CNS-BCOR ITD) are aggressive malignancies recently included in the 2021 WHO Classification of CNS tumors. This entity is characterized by ITDs within the PUFD domain of BCOR, potentially interfering with protein-protein interactions and preventing non-canonical polycomb repressive complex 1.1 (ncPRC1.1) complex formation. Additionally, other BCOR alterations like frame shift mutations and gene fusions have been described. However, the underlying molecular mechanisms promoting tumor aggressiveness remain unknown. We established cell models from one patient harboring a BCOR frameshift mutation and another one with a concomitant BCORL1-fusion. Two additional models were derived from a patient with a CNS-BCOR ITD tumor. Multidrug screening uncovered high sensitivity against defined receptor tyrosine kinase (RTK) inhibitors (TKIs). In detail, ponatinib, nintedanib, and dovitinib reduced cell viability at half maximal inhibitory concentrations (IC50) in the low micro-molar range (&amp;lt;2.5 µM). Expression analyses of the respective TKI targets suggested fibroblast growth factor receptor 3 (FGFR3) and platelet derived growth factor receptor A (PDGFRA) as central players in this response. RTK inhibition resulted in strongly impaired downstream MAPK and Pi3K/AKT signaling. Vice versa, exposure to the RTK ligands bFGF and PDGFAA increased S6, Erk and Akt phosphorylation. Next, we treated two patients – one with a BCOR frame shift mutation/BCORL1-gene fusion and one with an ITD with nintedanib – within a multimodal treatment approach and achieving complete remission and disease stabilization, respectively. Ultimately, we analyzed respective RTK ligands in patient cerebral spinal fluid (CSF) and found FGF18 and PDGFA to correlate with tumor treatment response and progression. Summarizing, we uncover a central role of defined RTK signaling modules in the malignant phenotype of CNS-BCOR-ITD and tumors harboring BCOR alterations and elucidate their potential as therapeutic targets. Currently, we aim to dissect the interconnection between BCOR/BCORL1 alterations and RTK hyperactivation.
DIPG-11. DIPGs show robust MHC class I expression but low lymphoid and high myeloid infiltration partly reversible by DNA methyltransferase inhibition
Authors: Deepak Mishra, Jie Wang, Chun-Yu Chen, Xiaoting Zhu, Shiva Senthil Kumar, Todd McHugh, Timothy Cripe, Maryam Fouladi, Rachid Drissi
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine gliomas (DIPGs) are the most aggressive tumors of the central nervous system in children. Median survival of patients is less than one year post-diagnosis. Radiotherapy remains the only standard treatment but is rarely curative. Immunotherapy is an emerging and promising treatment strategy for children with DIPG. However, general immunotherapy has not lived up to its promise to treat many cancers, including DIPGs, in part due to incomplete understanding of the barriers posed by the tumor microenvironment. We therefore evaluated the immune cell infiltration in a syngeneic mouse model of DIPG and in DIPG tumors collected from patients. We evaluated the expression profiles of T lymphocytes and myeloid cell markers in a cohort of 28 DIPG tumors compared to matched normal tissue specimens. Our data indicate that the expression of MHC I components in DIPG tumors is similar to that of matched normal tissue. Moreover, the well-known immune checkpoint, PD-L1, was not overexpressed in DIPG tumors. Using immunohistochemistry, we demonstrated only rare infiltration of lymphocytes but high enrichment of myeloid cells in tumor tissue. We found similar results in a syngeneic mouse model of DIPG. Collectively, our results indicate that DIPG tumors harbor rare lymphocytes and are enriched in myeloid cells. Recent studies have demonstrated that DNA methyltransferase inhibitors prime some tumors for more effective checkpoint blockade by activating expression of human endogenous retroviruses and sparking a T-cell mediated immune response through a process called “viral mimicry.” We tested the effect of decitabine in a syngeneic mouse model of DIPG. Decitabine reduced the tumor growth kinetics compared to vehicle but was unable to induce the recruitment of lymphoid cells in DIPG tumors. Importantly, we observed a noticeable reduction in the myeloid component of the DIPG microenvironment suggesting a possible role of myeloid cells in tumor growth and progression.
DIPG-55. Increasing the drug-tumor resonance time in DMG murine models significantly extends survival
Authors: Erica Power, Liang Zhang, Julian Rechberger, Juhee Oh, William Elmquist, David Daniels
Journal: Neuro-Oncology (2022)

Abstract H3K27-altered diffuse midline glioma (DMG) is a uniformly lethal CNS cancer that predominately occurs in children. In the last decade, while studies revealing the molecular underpinnings of the disease have paved the way for novel therapeutic strategies, this tumor remains a death sentence. Our lab and others have identified numerous drugs of high interest for treating this devasting disease, however, every trial has failed to show benefit. Is our failure to translate these laboratory findings due to the fact we have not found the right drugs or treatment regimens yet? Or is this a failure to get the drugs to the tumor? Or is this simply a very bad disease to treat? The answer is likely multifactorial. Our lab, in collaboration with others, have strong data to show that simply getting drugs to the tumor will not result in a positive benefit. Most drugs are rapidly cleared from their target space. Utilizing techniques that increase the drug-tumor resonance time is necessary to translate our basic science findings to our patients. Picking the right drug and the delivery mechanism is not enough for a positive effect. Here, we assessed the efficacy of a previously identified inhibitor, alisertib, delivered by short-term convection-enhanced delivery or a continuous osmotic pump and found that continuous, direct delivery results in a significant increase in survival (p = 0.0002). Furthermore, long-term survivors showed a decreased tumor burden and on-target drug effects. These data support that translation into patients must consider three factors: 1) selection of a potent therapy, 2) selection of the proper delivery method for that therapy, 3) modulation to ensure that the therapy remains in the targeted tissue long enough for desired effect. Keeping these basic tenets at the forefront of development may finally lead to a more effective treatment strategy for this devastating disease
IMMU-17. Comprehensive immunological gene expression profiling of pediatric brain tumors
Authors: Adrian Levine, Liana Nobre, Scott Milos, Monique Johnson, Benjamin Laxer, Scott Ryall, Robert Siddaway, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2022)

Abstract Immunotherapy, predominantly through immune checkpoint inhibition (ICI), has had incredible success in treating some metastatic cancers, however, outside of rare cases of mismatch repair deficient (MMRD) gliomas, brain tumors have not had consistent responses to ICI. This can be attributed to a variety of factors including a low tumor mutation burden, lack of T cell infiltrates, and the CNS immune privilege. There are numerous strategies to target the tumor immune microenvironment (TIME) beyond ICI, include CAR-T cells, tumor vaccines, and myeloid cell modulation. The investigation of these depends critically on detailed characterization of the cell populations and interactions in the CNS TIME. We developed a 103 gene NanoString immune-oncology gene expression panel that includes markers reflecting selected cell types, therapeutic targets, and cellular pathways, as well as the 18-gene Tumor Inflammation Signature, a well validate biomarker for ICI response. We have used this to characterize over 500 brain tumors, including a diverse set of 227 pediatric low-grade gliomas (LGG), 86 MMRD gliomas, 47 diffuse intrinsic pontine gliomas (DIPG), 26 ependymomas, 36 medulloblastomas, 70 adult gliomas, and 35 non-tumor brain samples. Our results demonstrate a broad range of immunologic states, including within groups of tumors with the same genetic driver alteration. In pediatric LGG with BRAF V600E, there was clear histologic correlation with immune status, as glioneuronal tumors had substantial upregulation of T cell markers and regulatory genes, while diffuse astrocytomas had a near normal immune profile. In DIPG there was strong upregulation of macrophage markers, contradicting prior reports that have characterized these tumors as immunologically neutral. In a set of MMRD gliomas treated with ICI we identified several differentially expressed genes correlating with therapeutic response, including CCL4, CXCL9, and HGPD. In sum, this provides a characterization of diverse immune activation states across pediatric gliomas and other brain tumors.
Single cell RNA-seq analysis reveals involvement of the interferon-I pathway and cellular senescence in calcific progression of human aortic valve cells
Authors: SF Ferrari, MA Agrifoglio, JM Manteiga, FG Giannese, MP Pesce
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ricerca corrente Introduction Valve interstitial cells (VICs) are heterogeneous fibroblast-like cells populating the aortic valve (AoV), involved in the extracellular matrix homeostasis. Under pathological conditions, VICs acquire the phenotype of calcific cells causing calcific aortic valve disease (CAVD) [1]. Purpose In order to find distinctive traits of the phenotype in calcific VICs, we employed single cell RNA-sequencing (scRNASeq) to compare the gene expression signatures of VICs from stenotic AoVs (sVICs) vs. valves with insufficiency (iVICs), a pathology characterized by a lower level of calcification. Methods Before being used for scRNAseq profiling, VICs from the two pathological settings were amplified for three passages, after which they were loaded into the Drop-seq platform that encapsulated them in oil droplets with lysis buffer and barcoded primer beads. Beads were then subjected to reverse transcription, followed by library preparation. Libraries were sequenced with a coverage ranging from 50,000 to 100,000 reads per cell. Results A total of 5844 iVICs and 5610 sVICs were successfully separated and barcoded. Four independent VICs donors/pathology were processed and UMAP representation/clustering of cells coming from the eight samples identified the existence of 8 distinct cellular phenotypes, including embryonic progenitor mesenchymal (EMBVICs), ‘activated’ (ACVICs), ‘osteoblastic’ (OBVICs) and ‘quiescent’ (QVICs). The analysis of the cellular composition did not reveal substantial differences in the abundance of the different phenotypes in the two pathologies. On the other hand, differential gene expression followed by functional pathways enrichment showed a significant upregulation in sVICs vs. iVICs of genes/pathways related to Interferon-I (INF-I) in all the identified cellular phenotypes with the exception of QVICs. These included e.g for ACVICs, IFITM1 (log2FC = 1.76 P=3e-101), IFI6 (log2FC = 2.38; P = 1e-69), IFITM3 (log2FC 0.9 P = 5e-58), ISG15 (log2FC = 1.7 P= 4e-53) and IFI27 (log2FC = 1.54 P = 6e-41) genes. Conclusions This study reveals the involvement of the interferon-I pathway signaling in CAVD, supporting an autophagic/inflammatory/senescent phenotype switching in relevant VICs types resident in the human AoV.
Rates of pathogenic variants in common cancer genes among different racial/ethnic groups.
Authors: Peter D. Beitsch, Chloe Wernecke, Steven Cai, Eric Allen Brown, Krista Ortega, Vicky Zhu, Rakesh Patel
Journal: Journal of Clinical Oncology (2022)

10515 Withdrawal Notice: Abstract 10151 by Beitsch et al, entitled "Rates of pathogenic variants in common cancer genes among different racial/ethnic groups," was withdrawn by the authors from presentation and publication. As they were preparing for presentation at the meeting, the authors discovered additional data that potentially altered the abstract's conclusions. The abstract was withdrawn on May 13, 2022.